Authors
Arghya Bhattacharya, Hailah M Almohaimeed, Waheeb Sami Aggad, Amany I Almars, Osama Mohammed Abdulaziz Altowaijri, Hadeel Abdulrahman Waggas, Nuha M Bauthman, Zuhair M Mohammedsaleh, Tahani Ahmad ALMatrafi, Fayez M Saleh, Daniel Ejim Uti
Published in
Acta neuropathologica communications. Volume 14. Issue 1. Jun 02, 2026. Epub Jun 02, 2026.
Abstract
Disease progression in Parkinson's disease has been driven by extracellular α-synuclein prion-like seeding throughout the course of the disease and therefore not just by the intracellular accumulation of the protein in isolated aggregates. Current therapies utilizing PROTACs cannot address the extra-cellular effects of α-synuclein spreading in this manner. This article proposes PolyTACs (Polymeric Lysosome-Targeting Chimeras) as hybrid antibody-polymer conjugates which use neuronal exofacial thiol groups produced because of DJ-1/GSH dysregulation to capture α-synuclein pathological conformers before they can be derepressed (seeded pathological aggregates) into the cytoplasm. The hybridity of these antibodies (oligomers and fibrils) combined with pyridyl disulfide linkages in the multi-valent polymer allows these compounds to circumvent LTR co-option, and to be trafficked to lysosomes via a non-clathrin pathway. The delivery route for these agents is intended to be via intra-nasal, thereby bypassing many of the issues associated with delivery through the BBB. Delivery to patients will be guided by thiol profiling in cerebrospinal fluid to assist in inclusion-exclusion criteria for patients in prodromal trials. With these developments, it is anticipated that this new class of agent may provide a modular framework adaptable to other proteinopathies such as tau and TDP-43, pending further validation.
PMID:
42231395
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.
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